There’s an adage in total synthesis that “every nitrogen in a molecule adds one year to candidate’s PhD” – in other words “synthetic targets with nitrogens are challenging.” This saying also holds true to potential substrates for metathesis chemistry. It’s known that the ruthenium based Grubbs-type catalysts have excellent substrate compatibility1 and therefore are utilized frequently in pharmaceutical and natural product syntheses.2 However, the presence of nitrogens can present a challenge, even for modern metathesis catalysts.3,4
Molecules containing unprotected amines can be difficult metathesis substrates because of the nitrogen’s lone pair ability to coordinate to the ruthenium catalyst. Often functional group masking or protection is applied to increase a substrate’s compatibility toward metathesis.5 Alternatively, additives such as acid can be added to complex problematic electron lone pairs without adversely affecting catalyst performance.6
Scheme 1. Ring closing metathesis of diene 1
|Entry||Catalyst||Catalyst Loading||Additive||Time||trans : cis||Yield (%)|
|1||Grubbs 2nd Gen.||25 mol%||–||36 h||–||–|
|2||Grubbs 2nd Gen.||10 mol%||HCla||3 h||85:15||60|
aReaction contained 5 equiv. of 4 M methanolic HCl
Recently, William and Lee demonstrated the utility of acidic conditions to facilitate ring closing metathesis of a kinase inhibitor.7 The highly chelating guanidine moiety present in their target molecule SB1518 presented a particularly difficult challenge for the ring closing metathesis of diene 1 (Scheme 1). As expected, the nitrogen dense substrate was unreactive toward Grubbs 2nd Gen. catalyst at loadings up to 25 mol% for 36 h. However, the authors were able to lower the loading of catalyst and decrease the reaction time by adding HCl. To their delight, the acidic conditions provided a yield of 60% enriched in the desired trans stereochemistry.
This report nicely displays how the use of additives can facilitate the in situ protection of troublesome functional groups. In order to overcome the complication of metal chelation, cumbersome alternative routes have sometimes been devised to effectively incorporate metathesis. However, this doesn’t have to always be the case, and over the last decade groups have demonstrated elegant solutions to these problems through the use of additives.
1 Trnka, T. M.; Grubbs, R. H. The Development of L2X2Ru=CHR Olefin Metathesis Catalysts: An Organometallic Success Story. Acc. Chem. Res. 2001, 34, 18-29.
2 (a) Horváth, A.; Farina, V. Ring-Closing Metathesis in the Large-Scale Synthesis of Pharmaceuticals. In Handbook of Metathesis, 2nd Ed. Grubbs, R. H., Wenzel, A. G.; O’Leary, D. J., Khosravi, E., Eds.; Wiley: Hoboken, 2015; pp 633-658. (b) Cossy, J., Arseniyadis, S., Meyer, C., Eds. Metathesis in Natural Product Synthesis: Strategies, Substrates and Catalysts. Wiley: Hoboken, 2010.
3 All Things Metathesis. http://allthingsmetathesis.com/metathesis-of-amine-containing-compounds/ (accessed October 21, 2015)
4 All Things Metathesis. http://allthingsmetathesis.com/reactions-amines-hoveyda-grubbs-2nd-generation/ (accessed November 19, 2015)
5 Compain, P. Olefin Metathesis of Amine-Containing Systems: Beyond the Current Consensus. Adv. Synth. Catal. 2007, 349, 1829-1847.
6 (a) with Lewis acids: Yang, Q.; Xiao, W.-J.; Yu, Z. Lewis Acid Assisted Ring-Closing Metathesis of Chiral Diallylamines: An Efficient Approach to Enantiopure Pyrrolidine Derivatives. Org. Lett. 2005, 7, 871-874. (b) with mineral acids: Woodward, C. P.; Spiccia, D.; Jackson, W. R.; Robinson, A. J. A simple amine protection strategy for olefin metathesis reactions. Chem. Comm. 2010, 47, 779-781.
7 William, A. D.; Lee, A. C.-H. Acid Mediated Ring Closing Metathesis: A Powerful Synthetic Tool Enabling the Synthesis of Clinical Stage Kinase Inhibitors. CHIMIA 2015, 69, 142-145.